Shock and Awe: A dynamic approach to Critical Care Symposium October 28, 2017 Anna Perrello, RPA-C, MPAS Brian Kersten, PharmD, BCCCP, BCPS Disclosures • Brian Kersten o Nothing to disclose • Anna Perrello o Nothing to disclose Objectives • Identify and explain the physiology of various states including distributive, cardiogenic, obstructive and hypovolemic. • Discuss advantages and limitations to static and dynamic predictors of volume responsiveness. • Recognize techniques related to visualization of basic structures and medium identification during bedside ultrasonography. • Evaluate treatment options for shock states using dynamic measures for fluid resuscitation

Shock • A heterogenous syndrome best defined as circulatory failure

o Originates from mismatch between oxygen delivery (DO2) and oxygen consumption (VO2)

• Often becomes apparent in setting of arterial

Differentiating Shock

Systemic Mixed Wedge Cardiac vascular venous pressure output resistance oxygen Hypovolemic - Hemorrhage ↓ ↓ ↑ ↓ - Dehydration Cardiogenic - Myocardial infarction ↑ ↓ ↑ ↓ - Arrhythmia - Cardiomyopathy Obstructive - Pulmonary embolism ↑↔ ↓ ↑ ↓ - Tension pneumothorax - Distributive - - ↑↔ ↑ ↓ ↑ - Neurogenic - Myxedema coma - Post-cardiopulmonary bypass Goals of Therapy in Shock • Restore effective tissue perfusion and normalize cellular metabolism by ensuring systemic oxygen delivery by 1. Aggressive and appropriate fluid resuscitation 2. Supporting CO and MAP • Above are titrated to individual endpoints and used together to assess adequacy of resuscitation 1. Markers suggesting adequate tissue perfusion 2. Markers suggesting adequate intravascular volume 3. Target MAP Shock and Awe • Military doctrine of rapid dominance Question •Global (macrocirculatory) oxygen

delivery (DO2) can be best approximated by which variable?

1. Arterial partial pressure of oxygen (PaO2)

2. Arterial oxygen saturation (SaO2) 3. Hemoglobin 4. Systemic vascular resistance (SVR) 5. Stroke volume (SV)

Global Tissue Perfusion • ‘Macrocirculation’

o DO2 = CO x CaO2 o DO2 = (SV x HR) x ([0.0138 x Hgb x SaO2] + [0.0031 x PaO2]) • Increasing hemoglobin and oxygen produce minimal changes in oxygen delivery • rate is generally at maximum compensation, therefore

o DO2 = SV x (HR) x ([0.0138 x Hgb x SaO2] + [0.0031 x PaO2])

• Regional tissue perfusion (microcirculation)

• Not predicted by DO2

Assessing perfusion

Physical Exam Laboratory • Mean arterial pressure • Lactate • Mentation o Cerebral perfusion • pH, pCO2 and HCO3 • Urine output • SCVO or SVO (>0.5ml/kg/hr) 2 2 • Capillary refill • Skin perfusion/mottling • Cold (or warm) extremities • Generalized edema o Pulmonary edema • Intra-abdominal pressure Volume Challenge • Reserved for hemodynamically unstable patients with three advantages 1. Opportunity to quantitate response during infusion 2. Prompt correction of fluid () deficits 3. Minimizing risk of volume overload

• Only ~50% of hemodynamically unstable patients are fluid responsive after initial resuscitation o Aggressive and overzealous fluid administration can lead to severe tissue edema and compromised organ function

Vincent JL. Crit Care Med 2006; 34:1333-1337 Marik PE. Crit Care Med 2013; 41:1774-1781 Question •Which of the following is best to utilize for quantifying a response to a volume challenge? 1. (CVP) 2. Mean arterial pressure (MAP) 3. Pulmonary capillary wedge pressure (PCWP) 4. pressure variation (PPV) 5. Urine output Stroke Volume • Dependent on preload and contractility in shock

Frank-Starling Curve

Stroke volume Stroke

Ventricular preload Volume responsiveness - Static

CVP = RAP = RVEDP = RVEDV = RV Preload ≈ PCWP = LVEDP = LVEDV = LV Preload

Measure* Premise Limitations Takeaway

Central venous CVP surrogate for CVP or ΔCVP does not DO NOT USE pressure (CVP) PCWP & correlate with intravascular PCWP = LVEDP volume or stroke index/cardiac (and thus stroke output volume) Pulmonary capillary PCWP = LVEDP LVEDP can be altered DO NOT USE wedge pressure independently of LVEDV; does (PCWP) not

*Other measures: left ventricular end diastolic area (LVEDA), right ventricular end diastolic volume (RVEDV) similar concerns

Kumar A. Crit Care Med 2004; 32:691-699. Marik PE. Chest 2008; 134:172-178 Marik PE. Crit Care Med 2013; 41:1774-1781 CVP & PCWP and Cardiac Output

Osman D. Crit Care Med 2007; 35:64-68 Dynamic Measurements of Fluid Responsiveness

• Dynamic measures are used to exploit the existing relationship between heart and lungs during • To evaluate a patient’s location on the Frank- Starling curve, the following dynamic measures can be used: o Stroke Volume Variation (SVV) o Pulse Pressure Variation (PPV)

o IVC Diameter Variation (∆DIVC)

Effects of Mechanical Ventilation on Intrathoracic Structures

+Intrathoracic Pressure

-Intrathoracic Pressure

Compliant Heart (Fluid Responsive)

Non-Compliant Heart (Not Fluid Responsive) Stroke Volume Variation (SVV)

• Procedure: o is placed, and the change in area under the arterial wave form during respiratory variation is compared

• ∆SVV 12-13% correlated with an increase of CO ≥ 15% after volume expansion, was highly predictive of fluid responsiveness1

SVV Sensitivity 0.82

Specificity 0.86

1Marik, PE, et al. Stroke volume variation and fluid responsiveness. A systematic review of the literature. Critical Care Med 2009; 37; 2642-7. “Advanced Parameters: SVV, PPV.” Change Region, Maquet Getinge Group, www.maquet.com/uk/services/advanced-monitoring-parameters/svv-ppv/. September 2 2017. Pulse Pressure Variation (PPV)

• Procedure: o Arterial line is placed, calculated difference (%) of pulse pressure between inspiration and expiration

• ∆PPV 12-13% correlated with an increase of CO ≥ 15% after volume expansion, was highly predictive of fluid responsiveness1

PPV Sensitivity 0.89

Specificity 0.88

1Marik, PE, et al. Stroke volume variation and fluid responsiveness. A systematic review of the literature. Critical Care Med 2009; 37; 2642-7. “Advanced Monitoring Parameters: SVV, PPV.” Change Region, Maquet Getinge Group, www.maquet.com/uk/services/advanced-monitoring-parameters/svv-ppv/. September 2 2017. IVC Variation

• Non-invasive measure to assess for fluid responsiveness in mechanically ventilated patients • Procedure: o 2D Echocardiography is used, IVC visualized in subxiphoidal view, measurements made in M-Mode during respiratory cycle at ~3cm from right atrium

o Difference calculated as ∆DIVC as a percentage

• ∆DIVC 12-18% with subsequent increase of CO ≥ 15% after volume expansion, correlated with fluid responsiveness3,4 o Positive Predictive Value: 93% o Negative Predictive Value: 92%

3Feissel, M. et al. Intensive Care Med (2004) 30: 1834.http://doi-org.gate.lib.buffalo.edu//100.1007/s00134-004-2233-5 4Barbier, C. et al. Intensive Care Med(2004) 30:1740. Http://doi-org.gate.lib.buffalo.edu/10.1007/s00134-004-2259-8 Identification of Structures and Mediums on Ultrasound

• White: Hyperechoic, often dense/calcified tissue; pericardium, diaphragm

• Black: Anechoic; fluid; , pleural fluid

• Light/Dark Gray: Hypoechoic, isoechoic; organs or structures, soft tissue, may indicate sluggish blood flow, thrombus

• Air: White/gray, STRONG reflector of sound waves, impedes visibility, often a limitation during bedside evaluation Identification of Structures and Mediums on Ultrasound

2

3 1

Transducer placed on left chest, along midaxillary line Identification of Structures and Mediums on Ultrasound

RA LA LV

Parasternal Long Axis Identification of Structures and Mediums on Ultrasound

Transducer placed subxiphoid view IVC Variation

∆DIVC ∆DIVC Inferior Vena Cava Variation to Assess for Fluid Responsiveness

Is this patient likely to be fluid responsive?

∆DIVC(%)=[(IVCDb-IVCDa)/IVCDb]x100

∆DIVC(%)=[(2.30-2.22)/2.22]x100=3.6% Limitations of PP, SV and IVC Variation

• Limitations:

o Patient must be mechanically ventilated with a Vt of at least 8ml/kg of IBW o No arrhythmias present o Passive ventilation o No increase in IAP or open chest o Requires arterial line placement (PPV and SVV) o Required Hemodynamic Monitoring Device (SVV) o Experience of ultrasonographer (IVC Variation)

Passive Leg Raise

• Non-invasive measure to assess for fluid responsiveness in spontaneously breathing patients • PLR to 30˚ simulates ~300cc fluid bolus to the patient that is easily reversible

• Procedure: o Patient is placed in a supine position, passive leg raise of 30˚, returned to supine position, administered 500cc NS o HR, BP and aortic flow velocity measured at each interval

Passive Leg Raise

• Aortic Flow Velocity (marker of SV) measured with bedside echocardiography, an increase of CO and SV >12% was noted to be significant and correlated with fluid responsiveness2

Sensitivity Specificity CO 63% 89% SV 69% 89%

• Limitations: o Good echocardiographic widows required for evaluation of SV and CO o Advanced echocardiographic skills o Technically difficult in many ICU patients

2Maizel, J. et al. Intensive Care Med (2007) 33: 1133. http://doi.org.gate.lib.buffalo.edu/10.1007/s00134-007-0642-7 Summary of Static and Dynamic Measures

Method Technology Sensitivity, Specificity, AUC

Pulse pressure Arterial waveform Sensitivity 89% variation (PPV) Specificity 88% Stroke volume Pulse contour analysis Sensitivity 82% variation (SVV) Specificity 86%

IVC Variation (∆DIVC) Echocardiography Sensitivity 93% Specificity 92% Passive Leg Raise Echocardiography Sensitivity 63% Specificity 89% Central venous Central venous AUC: 0.55 (0.48-0.62) pressure (CVP) catheter 1 Case Study Case Study One

• 44 y/o F presents with SOB and 10/10 extremity pain with subsequent difficulty ambulating, and decreased urine output

• PMHx: o IVDA, currently on Suboxone o Anxiety o Fungemia ~6 months ago s/p full treatment course o H/o Empyema requiring thoracentesis

Case Study One •Vitals on admission : o HR: 154, Sinus o BP: 96/79, on 10mcg of Levophed infusion o Temperature: 36.6˚ o RR: 35-47 o Spo2: 97% on 50% Venti-Mask

Mg: 1.4 AST/ALT: 48/17 Initial Labs: 132 101 61 79 Albumin: 2.5 3.3 15 3.27 Calcium: 8.2 12.5 3.2 69 U/a w/ Micro: 1+ leuk 36.7 VBG: 7.25/38/74/17 esterase, +26-100 Lactate: 2.9 leukocytes, +26-100 erythrocytes, few bacteria

Case Study One • Given additional 2L NS • Patient was intubated for respiratory failure • Started on Vanco, Zosyn, and Micafungin

• Repeat Labs: 12.1 2.9 57 36.3

131 91 60 87 ABG: 7.19/38/65/14 5.4 14 3.04 Lactate: 4.3 Case Study One

• Chest portable on admission :

Chest portable post-intubation:

Case Study One Parasternal Short Axis • Bedside US:

RV LV

RA LA LV

Parasternal Long Axis Case Study One

• Bedside US:

∆DIVC(%)=640%

Is the patient likely to be fluid responsive? Case Study One: Diagnosis

•Patient was treated for severe septic shock, additional 4L IVF given •Vasopressin added to Levophed gtt •Patient grew +2/2 Blood cultures for Gram Positive Cocci in clusters within 8 hours of admission Crystalloid vs colloid Trial Design Population Interventions Results Conclusion

SAFE Multicenter, Medical, surgical 4% albumin (n= RR death at 28 days No mortality 2004 randomized, intravascular 3497) 0.9% sodium 0.99 (95%CI; 0.91- difference in double-blind volume ICU chloride (n=3500) 1.09); Trends in heterogeneous resuscitation and trauma for and population against albumin CHEST Multicenter, Medical and HES 130/0.4 RR mortality at 90 No mortality 2012 randomized, surgical patients (n=3358) vs 0.9% days 1.06 (95%CI; 0.96 difference, but blinded, w/ NaCl (n=3384) -1.18). increased AKI parallel-group in ICU and RRT in HES 6S Multicenter, Medical and HES 130/0.4 (n=398) RR 90-day mortality Increased 2012 randomized, surgical patients vs Ringer’s acetate 1.17 (95% CI; 1.01- mortality and blinded, with severe (n=400) 1.36) favoring Ringer’s RRT with HES parallel-group sepsis in ICU CRISTAL Multicenter, Sepsis, trauma, Colloids (n=1414); No difference (25.4 vs No difference in 2013 randomized, hypovolemic Crystalloids (n=1443) 27%) in 28-day mortality for open-label shock in ICU mortality. Decreased hypovolemia in 90-day mortality ICU patients ALBIOS Multicenter, Severe sepsis 20% albumin & RR death at 28 days No mortality 2014 randomized, medical/surgical crystalloid (n=903) 1.0 (95% CI; 0.87-1.14); benefit open-label ICU vs crystalloid alone no difference at 90 (n=907) days Crystalloid vs colloid • No evidence from randomized trials that resuscitation with colloids reduces mortality compared with crystalloids o HES solutions may increase mortality and AKI • Avoid albumin and hypotonic solutions in TBI o Potential increased mortality due to increased intracranial pressure

Cochrance Database Syst Rev. 2013: 28;2 CD00D567 NEJM 2004; 350:2247-56 Question •In microcirculatory models interstitial edema (‘third-spacing’) is influenced mainly by

1. Low capillary oncotic pressure (πP) 2. High capillary hydrostatic pressure (PC) 3. High interstitial oncotic pressure (πI) 4. High interstitial hydrostatic pressure (PI)

Starling Forces

Net filtration pressure =

(PC – PI) – (πP – πI) Endothelial Glycocalyx • Acellular layer lining the • Acellular layer lining the intravascular intravascular endothelium endothelium o Web of membrane-bound o Web of membrane-bound glycoproteins and glycoproteins and proteoglycans proteoglycans o Hydrophilic and anionic • Colloid oncotic • Colloid oncotic pressure across the EGL pressure across the EGL opposes, but does not opposes, but does not reverse, filtration rate reverse, filtration rate by transfusion colloids by transfusion colloids

Myburg N Engl J Med 2013; 369(13):1243-51. Woodcock Brit J Anaesth 2012; 108 (3); 384-94. Endothelial Damage Glycocalyx Implications 1. Glycocalyx ‘traps’ plasma water in hydrophilic composition o Crystalloid : colloid is ~1.3:1 o Colloid administration likely ‘dehydrates’ glycocalyx increases plasma volume (transiently) 2. Fluid extravasation predominately dependent on capillary hydrostatic pressures

o Minimize rapid increases in PC • Small boluses

• Alpha agonists – constricts pre-capillary arterioles attenuating PC 3. Hypoalbuminemia correction is of no clinical benefit o Indicator of disease severity 4. Hyperoncotic albumin solution doesn’t improve pulmonary edema

Myburg N Engl J Med 2013; 369(13):1243-51. Woodcock Brit J Anaesth 2012; 108 (3); 384-94. Crystalloids

Lactated Plasma-Lyte & Plasma 0.9% NaCl Ringer’s Normosol Sodium (mmol/L) 140 154 130 140

Chloride (mmol/L) 102 154 109 98

Potassium (mmol/L) 4 - 4 5

Calcium (mmol/L) 5 - 3 -

Magnesium (mmol/L) 2 - - 3

Buffer (mmol/L) Bicarbonate Acetate (27) - Lactate (28) (24) Gluconate (23) pH 7.4 5.7 6.4 7.4 Osmolality 290 308 273 295 (mOsm/L) Hyperchloremia 1. High chloride concentration filtered across glomerulus 2. Increased chloride concentration in tubule 3. Macula densa senses increased chloride concentration 4. Macula densa releases local mediators stimulating afferent arteriole 5. Afferent arteriole constricts

Decreased hydrostatic pressure and GFR 0.9% NaCl vs Chloride restrictive

Trial Design Population Interventions Results Conclusion

Yunos Single center, 22-bed mixed Chloride-liberal vs Restrictive Restricting IV 2012 prospective, med-surg ICU chloride-restrictive associated with less chloride open-label, in 6 months periods RIFLE-defined AKI decreases before-and-after 2008 and 2009, and RRT and lower incidence of AKI respectively serum creatinine rise and RRT SPLIT Double-blind, 4 New Alternating 7-week AKI at 90 days was Buffered 2015 cluster Zealand ICUs blocks of Plasma- 9.6% PL and 9.2% NS crystalloid did not randomized, (3 mixed med- Lyte or 0.9% saline with a RR 1.04 [95% reduce the risk of double cross- surg, 1 with two crossovers CI 0.80-1.36]. AKI compared to over cardiothoracic No difference in RRT saline and vascular) PLUS Multicenter, ICU patients Plasma-Lyte vs Expected N/A Recruiting blinded, requiring fluid 0.9% NaCl completion 2021 randomized resuscitation 2 Case Study Case Study Two

• 67 y/o F presents s/p PEA arrest for 10 minutes, presumed septic shock secondary to unknown source. Patient ventilated and sedated upon admission, on Levophed gtt at 15mcg/hr. • Family denies prodrome of fevers/chills/n/v/d, or CP, but reported +general malaise and increased SOB x3 days.

• PMHx: o Hyperlipidemia o DM o HTN o CAD

Case Study Two • Vitals on admission : o HR: 72, NSR o BP: 101/54 on Levophed gtt at 15mcg/hr o Temperature: 37.5˚ o RR: 22 o Ventilated, Spo2 96% on Fio2 of 80%, PEEP of 8 Troponin: 1.31 CK-MB: 8 Initial Labs: 144 109 65 Mg: 1.2 83 AST/ALT: 101/132 4.6 17 2.25 Calcium: 8.2 10.3 18.9 225 30.9 VBG: 7.25/34/61/16 U/a w/ Micro: -6-25, -Nitrites, -Bacteria, +Small protein Lactate: 2.4 U/o: 20cc since admission

Case Study Two

• Patient given 2L IVF in the Emergency Department • Started on Vanco and Zosyn for severe septic shock

Chest portable on admission:

ECG on admission: ST depressions in II, II and aVF with

TWI in V5 and V6

Repeat labs: Troponin(8hr): 16.31 CK-MB: 25

Case Study Two

• Bedside US continued:

RV LV

Parasternal Short Axis Case Study Two

• Bedside US was completed :

RV LV RA LA

Subcostal view Case Study Two

• Bedside US:

∆IVCD(%)=6.8%

Is the patient likely to be

fluid responsive? A 2.45 0.01s B 2.63cm Case Study Two: Diagnosis

• Patient diagnosed with secondary to acute myocardial infarction • Additional IVF administration was stopped • Vasopressin was added for to Levophed infusion “Fluid Safety” • Earlier initiation of vasopressors may be warranted

• Volume overload compromises organ blood flow

• Most clinicians would likely support conservative therapy once ‘adequate resuscitation’ achieved

• Interestingly, recent trials SSSP-2 and FEAST suggest bolus fluid is harmful o Both in sub-Saharan Africa, one in children

What is practiced? • FENICE Study • Clinicians relied heavily • Half of patients with on hypotension and BP negative response to response fluid challenge • Half of patients had no received further fluid hemodynamic value to measure response o CVP used most often

• Authors conclude “current practice and evaluation of fluid challenge in critically ill patients seems to be arbitrary”

Cecconi Intensive Care Med; 2015(41):1529-37. 3 Case Study Case Study Three

• 58 y/o M presents with chief complaint of SOB x 3 weeks, progressively worsening in the past 3 days o ROS: +cough with white sputum production, +chest pressure, +intermittent chills, +dyspnea on exertion.

• PMHx: o HTN o Raynaud’s Disease o Tobacco use; quit 30 years ago Case Study Three

• Vitals on admission : o HR: 107, NSR o BP: 121/74 o Temperature: 36.3˚ o RR: 19-26 o Spo2: 80% on Room air

Mg: 2.2 Initial Labs: 118 84 44 AST/ALT: 23/17 110 Albumin: 3.9 5.9 17 1.74 Calcium: 9.7 14.7 14.8 339 ABG: 7.47/24/62/21 Troponin: 0.02 41.3 Lactate: 2.4 BNP: 69

Case Study Three

• Given 3L NS, placed on4L NC, Spo2 improved to 96% • Started on Ceftriaxone and Azithromycin for CAP • Developed worsening SOB overnight

Chest portable on admission Chest portable 8 hours later

Case Study Three

• Bedside US was completed :

RA LA LV

Parasternal Long Axis Case Study Three Subcostal view • Bedside US was completed :

RV LV RA LA

RV LV

Parasternal Short Axis Case Study Three

• Official Echo was completed which revealed large pericardial effusion with + early diastolic collapse of RV and dilated IVC

Case Study Three: Diagnosis

• Cardiac Tamponade o Pericardial Window; 750cc of serosanguineous fluid was removed o Pericardial fluid revealed malignant cells

*Remember, a patient in tamponade is preload dependent, but when using IVC variation to assess for volume status, would show a dilated IVC with little variation due to obstructive shock. Summary • Goal of shock is to restore effective tissue perfusion beginning with fluid challenge o Assessing response is crucial • Dynamic >> static • Ultrasonography is an excellent modality for undifferentiated shock as it can provide data regarding type of shock, need for therapeutic intervention and response to resuscitation • Crystalloids are reasonable first-line agents for fluid resuscitation in most patients